Mechanisms of early metastatic spread: Epigenetic plasticity and selection of advantageous genotypes

早期转移扩散的机制：表观遗传可塑性和有利基因型的选择

• 批准号: 116325575
• 负责人: Professor Dr. Christoph Klein
• 金额: --
• 依托单位: Lehrstuhl für Experimentelle Medizin und Therapieverfahren
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/116325575?language=en
• 关键词: Mechanisms; early; metastatic; spread; Epigenetic

Analysing the Balb/NeuT mouse model of breast cancer, we found that metastatic dissemination of cancer cells takes place shortly after malignant transformation. Already one to four 4 weeks after induction of the transgene, we detected disseminated tumour cells (DTC) in lung and bone marrow. Surprisingly, DTCs were found in bone marrow before macroscopic or microscopic tumours were detectable. No increase of DTCs in bone marrow was observed with increasing size of the primary tumours neither in mice nor in patients. First molecular studies revealed an upregulation of proteolytic enzymes and of the transcription factor Twist in early lesions that even exceeded the levels detectable in the invasion front of large carcinomas. In the proposed project we want to use the Balb/NeuT model and four other mouse models of our collaborators to identify the molecular mechanisms of early cancer spread. Candidate regulators will be tested on human samples. Central to our project is the attempt to precisely identify the invading and disseminating tumour cells and to provide a detailed description of their phenotype and genotype. Functional assays will test candidate regulators. We will also ask whether the physiological mechanisms of cancer spread seen in sporadically arising tumours are different to currently proposed mechanisms mostly identified in cell lines, which imply that metastatic dissemination is a late event.

分析乳腺癌的Balb/NeuT小鼠模型，我们发现癌细胞的转移性传播发生在恶性转化后不久。在转基因诱导后1至4周，我们在肺和骨髓中检测到播散性肿瘤细胞（DTC）。令人惊讶的是，在肉眼或显微镜下可检测到肿瘤之前，在骨髓中发现了DTC。在小鼠和患者中均未观察到骨髓中DTC随原发性肿瘤大小增加而增加。第一个分子研究揭示了蛋白水解酶和转录因子Twist在早期病变中的上调，甚至超过了在大型癌的侵袭前可检测到的水平。在拟议的项目中，我们希望使用Balb/NeuT模型和我们合作者的其他四种小鼠模型来确定早期癌症扩散的分子机制。候选监管机构将在人体样本上进行测试。我们项目的核心是试图精确识别入侵和传播的肿瘤细胞，并提供其表型和基因型的详细描述。功能测定将测试候选调节剂。我们还将询问在偶发性肿瘤中观察到的癌症扩散的生理机制是否与目前提出的主要在细胞系中鉴定的机制不同，这意味着转移性扩散是晚期事件。